생명과학회지 (Journal of Life Science)

  • 제19권4호
  • /
  • Pages.423-428
  • /
  • 2009
  • /
  • 1225-9918(pISSN)
  • /
  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
권호 표지
DOI QR코드

DOI QR Code

AMP-activated protein kinase가 셀레늄으로 처리된 3T3-L1 지방세포의 분화과정 억제에 관한 연구

AMP-activated Kinase Regulates Adipocyte Differentiation Process in 3T3-L1 Adipocytes Treated with Selenium

  • 박송이 (한남대학교 생명나노과학대학 생명과학과) ;
  • 황진택 (한국식품연구원) ;
  • 이윤경 (한남대학교 생명나노과학대학 식품영양학과) ;
  • 김영민 (한남대학교 생명나노과학대학 생명과학과) ;
  • 박옥진 (한남대학교 생명나노과학대학 식품영양학과)
  • Park, Song-Yi (Department of Biological Sciences, Hannam University Daedeok Valley Campus) ;
  • Hwang, Jin-Taek (Korea Food Research Institute, Functional Food Reserch center) ;
  • Lee, Yun-Kyoung (Department of Food and Nutrition, Hannam University Daedeok Valley Campus) ;
  • Kim, Young-Min (Department of Biological Sciences, Hannam University Daedeok Valley Campus) ;
  • Park, Ock-Jin (Department of Food and Nutrition, Hannam University Daedeok Valley Campus)
  • 발행 : 2009.04.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

셀레늄은 필수미네랄로 항산화작용 등의 체내 주요 작용을 수행한다고 알려져 있다. 만성질환 등의 예방과 치료 등의 바람직한 효능을 기대하여 섭취가 늘고 있어서 주목을 받고 있다. 셀레늄은 암의 억제나 혈중포도당조절 및 지방억제 등의 목적으로도 이용되고 있다. 이러한 다양한 연구에도 불구하고 지방세포를 이용한 지방세포분화나 지방세포사멸 촉진에 미치는 영향은 아직 연구되어 있지 않다. 셀레늄의 지방세포조절을 통한 분자기전에 대한 연구는 늘어가고 있는 비만이나 비만관련대사질환의 조절에 학문적 근거를 제공할 수 있다. 본 연구에서는 셀레늄이 AMP-activated protein kinase (AMPK)를 중심으로 지방 미분화세포인 3T3-L1 지방세포의 분화억제 및 분화된 세포의 사멸작용의 기전을 밝히고자 하였다. AMPK는 세포 내 에너지상태의 센서로 작용하는데 실제적으로 운동의 지방대사 촉진기능이 이 단백질에 기인한다는 사실이 밝혀지면서 각광을 받고 있다. 또한 시상하부에서 AMPK는 호르몬이나 영양소 등의 생리적인 인자들을 통합하고 식욕이나 신체에너지 대사를 총괄하는 물질로 대두되고 있다. 셀레늄을 지방세포의 분화과정에 처리하였을 때에 현저한 지방세포로의 분화가 억제되었고 이미 다 분화된 성숙된 지방세포에 처리하였을 때는 세포사멸(apoptosis)을 유도하는 것을 발견하였으며 이와 동시에 AMPK의 활성화 촉진 및 AMPK의 지질인 acetyl-CoA carboxylase의 $serine^{79}$를 인산화하는 것으로 나타났다. 또한 이러한 셀레늄의 지방세포분화 억제 능력은 AMPK의 활성화 합성물질인 AICAR나 포도의 폴리페놀인 레스베라트롤의 능력과 같은 정도의 억제능을 보여주었다. 또한 AMPK의 항 지방축적작용에서의 필수성을 알아보기 위하여 지방세포에 AMPK 활성화 물질인 AICAR와 억제물질인 Compound C를 사용하여 AMPK활성화를 측정하여 본 결과 지방세포분화와 지방축적의 억제과정에 있어서 AMPK가 필수적임을 밝혀내었다.

Selenium was investigated using human origin preadipocytes to see whether it possesses preventive or therapeutic effects for obesity. Unveiling the potential of selenium in the reduction of adipogenesis can help predict the therapeutic capabilities of selenium in obesity. In the present study, the molecular mechanism of the inhibition of adipogenesis by selenium was explored to unravel the involvement of the AMP-activated protein kinase. There is emerging evidence that AMPK, a sensor of cellular energy status, is a possible molecular target of controlling adipocyte differentiation on the basis of discovery that AMPK is responsible for the major metabolic responses to exercise, and integration of nutritional and hormonal signals to modulate feeding behavior or energy expenditure in the hypothalamus. Treatment of selenium resulted in inhibition of the adipocyte differentiation process and induction of mature apoptosis in 3T3-L1 adipocytes. We hypothesized that selenium may exert anti-adipogenic potential though modulating AMPK. We have found that selenium significantly activated AMPK and phosphorylated its substrate acetyl-CoA carboxylase ($ACC-serine^{79}$) during the inhibitory process of adipocytes. Also, the inhibition process of adipocyte differentiation by selenium was comparable to either reveratrol or a synthetic AMPK activator, AICAR (5-aminoimidazole-4-carboxamide-1-${\beta}$-D-ribofuranoside). To evaluate the involvement of AMPK in anti-lipogensis, we applied AICAR and Compound C, an AMPK inhibitor, to 3T3-L1-adipocytes and found that AMPK is required for the adipocyte differentiation blocking process. These results suggest that selenium has a potential to control adipogenesis and that this effect is mediated by AMPK, an essential kinase for both inhibition of adipocyte differentiation and apoptosis of mature adipocytes.

키워드

참고문헌

  1. Bays, H. E., J. M. Gonzalez-Campoy, G. A. Bray, A. E. Kitabchi, D. A. Bergman, A. B. Schorr, H. W. Rodbard, and R. R. Henry. 2008. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert. Rev. Cardiovasc. Ther. 6, 343-368 https://doi.org/10.1586/14779072.6.3.343
  2. Block, K. I., A. C. Koch, M. N. Mead, P. K. Tothy, R. A. Newman, and C. Gyllenhaal. 2008. Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. Int. J. Cancer. 123, 1227-1239 https://doi.org/10.1002/ijc.23754
  3. Browne, G. J., S. G. Finn, and C. G. Proud. 2004. Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J. Biol. Chem. 279, 12220-12231 https://doi.org/10.1074/jbc.M309773200
  4. Cherukuri, D. P. and M. A. Nelson. 2008. Role of reactive oxygen species (ROS) and JNKs in selenite-induced apoptosis in HepG2 cells. Cancer. Biol. Ther. 7, 689-696 https://doi.org/10.4161/cbt.7.5.5688
  5. Dagon, Y., Y. Avraham, and E. M. Berry. 2005. AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes. Biochem. Biophys. Res. Commun. 340, 43-47 https://doi.org/10.1016/j.bbrc.2005.11.159
  6. Daval, M., F. Foufelle, and P. Ferre. 2006. Functions of AMP-activated protein kinase in adipose tissue. J. Physiol. 574, 55-62 https://doi.org/10.1113/jphysiol.2006.111484
  7. Erbayraktar, Z., O. Yilmaz, A. T. Artmann, R. Cehreli, and C. Coker. 2007. Effects of selenium supplementation on antioxidant defense and glucose homeostasis in experimental diabetes mellitus. Biol. Trace. Elem. Res. 118, 217-226 https://doi.org/10.1007/s12011-007-0037-5
  8. Gao, S., K. P. Kinzig, S. Aja, K. A. Scott, W. Keung, S. Kelly, K. Chohnan, S. Strynadka, W. W. Smith, K. L. Tamashiro, E. E. Ladenheim, G. V. Tu, Y. Ronnett, M. J. Birnbaum, G. D. Lopaschuk, and T. H. Moran. 2007. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc. Natl. Acad. Aci. USA 104, 17358-17363 https://doi.org/10.1073/pnas.0708385104
  9. Gray, S. L. and A. J. Vidal-Puig 2007. Adipose tissue expandability in the maintenance of metabolic homeostasis. Nutr. Rev. 65, 7-12 https://doi.org/10.1301/nr.2007.jun.S7-S12
  10. Hardie, D. G., D. Carling, and M. Carlson 1998. The AMPactivated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu. Rev. Biochem. 67, 821-855 https://doi.org/10.1146/annurev.biochem.67.1.821
  11. Horman, S., G. Browne, U. Krause, J. Patel, D. Vertommen, L. Bertrand, A. Lavoinne, L. Hue, C. Proud, and M. Rider. 2002. Activation of AMP-activated protein kinase leads to the phosphorylation of elongation factor 2 and an inhibition of protein synthesis. Curr. Biol. 12, 1419-1423 https://doi.org/10.1016/S0960-9822(02)01077-1
  12. Huypens, P., E. Quartier, D. Pipeleers, and M. Van de Casteele. 2005. Metformin reduces adiponectin protein expression and release in 3T3-L1 adipocytes involving activation of AMP activated protein kinase. Eur. J. Pharmacol. 518, 90-95 https://doi.org/10.1016/j.ejphar.2005.06.016
  13. Hwang, J. T., I. J. Park, J. I. Shin, Y. K. Lee, S. K. Lee, H. W. Baik, J. Ha, and O. J. Park. 2005. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 338, 694-696 https://doi.org/10.1016/j.bbrc.2005.09.195
  14. Joens, R. G., D. R. Plas, S. Kubek, M. Buzzai, J. Mu, Y. Xu, M. J. Birnbaum, and C. B. Thompson. 2005. AMP-activated protein kinase induces a p-53 dependent metabolic checkpoint. Mol. Cell 18, 283-293 https://doi.org/10.1016/j.molcel.2005.03.027
  15. Kemp, B. E., D. Stapleton, D. J. Campbell, Z. P. Chen, S. Murthy, M. Walter, A. Gupta, J. J. Adams, F. Katsis, B. van Denderen, I. G. Jennings, T. Iseli, B. J. Michell, and L. A. Witters. 2003. AMP-activated protein kinase, super metabolic regulator. Biochem. Soc. Trans. 31, 162-168 https://doi.org/10.1042/BST0310162
  16. Kola, B. 2008. Role of AMP-activated protein kinase in the control of appetite. J. Neuroendocrinol. 20, 942-951 https://doi.org/10.1111/j.1365-2826.2008.01745.x
  17. Kola, B., A. B. Grossman, and M. Korbonits. 2008. The role of AMP-activated protein kinase in obesity. Front. Horm. Res. 36, 198-211
  18. Kubota, N., W. Yano, T. Kubota, T. Yamauchi, S. Itoh, H. Kumagai, H. Kozono, I. Takamoto, S. Okamoto, T. Shiuchi, R. Suzuki, H. Satoh, A. Tsuchida, M. Moroi, K. Sugi, T. Noda, H. Ebinuma, Y. Ueta, T. Kondo, E. Araki, O. Ezaki, R. Nagai, K. Tobe, Y. Terauchi, K. Ueki, Y. Minokoshi, and T. Kadowaki. 2007. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 6, 55-68 https://doi.org/10.1016/j.cmet.2007.06.003
  19. MacDougald, O. A. and S. Mandrup. 2002. Adipogenesis: forces that tip the scales. Trends. Endocrinol. Metab. 13, 5-11 https://doi.org/10.1016/S1043-2760(01)00517-3
  20. Meisse, D., M. Van de Casteele, C. Beauloye, I. Hainault, B. A. Kefas, M. H. Rider, F. Foufelle, and L. Hue. 2002. Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells. FEBS. Lett. 526, 38-42 https://doi.org/10.1016/S0014-5793(02)03110-1
  21. Mukherjee, P., T. J. Mulrooney, J. Marsh, D. Blair, T. C. Chiles, and T. N. Seyfried. 2008. Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain. Mol. Cancer 7, 37-51 https://doi.org/10.1186/1476-4598-7-37
  22. Shimomura, I., R. E. Hammer, J. A. Richardson, S. Ikemoto, Y. Bashmakor, J. L. Goldstein, and M. S. Brown. 1998. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 12, 3182-3194 https://doi.org/10.1101/gad.12.20.3182
  23. Song, X. M., M. Fiedler, D. Galuska, J. W. Ryder, M. Fernstrom, A. V. Chibalin, H. Wallberg-Henriksson, and J. R. Zierath. 2002. 5-Amino-imidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia. 45, 56-65 https://doi.org/10.1007/s125-002-8245-8
  24. Sorisky, A. 1999. From pre-adipocyte to adipocyte: differentiation-directed signals of insulin from the cell surface to the nucleus. Crit. Rev. Clin. Lab. Sci. 36, 1-34 https://doi.org/10.1080/10408369991239169

피인용 문헌

  1. Pear pomace water extract inhibits adipogenesis and induces apoptosis in 3T3-L1 adipocytes vol.8, pp.1, 2014, https://doi.org/10.4162/nrp.2014.8.1.33